1000341-27-4Relevant articles and documents
Design, synthesis and structure–activity relationship of indolylindazoles as potent and selective covalent inhibitors of interleukin-2 inducible T-cell kinase (ITK)
Wang, Xueying,Xue, Gang,Pan, Zhengying
, (2020)
Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays an important role in T cell signaling downstream of the T-cell receptor (TCR). Herein we report the discovery of a series of indolylindazole based covalent ITK inhibitors with nanomolar inhibitory potency against ITK, good kinase selectivity and potent inhibition of the phosphorylation of PLCγ1 and ERK1/2 in living cells. A computational study provided insight into the interactions between inhibitors and Phe437 at the ATP binding pocket of ITK, suggesting that both edge-to-face π-π interaction and the dihedral torsion angle contribute to inhibitors’ potency. Compounds 43 and 55 stood out as selective covalent inhibitors with potent cellular activity, which could be used as chemical tools for further study of ITK functions.
Synthesis and Biological Evaluation of 3-Arylindazoles as Selective MEK4 Inhibitors
Bergan, Raymond,Clutter, Matthew R.,Deibler, Kristine K.,Fowler, Graham,George, Mariam Donny,Gordon, Ryan,Mishra, Rama K.,O'Connor, Matthew,Scheidt, Karl A.,Schiltz, Gary E.,Vagadia, Purav P.
supporting information, p. 615 - 620 (2019/02/25)
Herein we report the discovery of a novel series of highly potent and selective mitogen-activated protein kinase kinase 4 (MEK4) inhibitors. MEK4 is an upstream kinase in MAPK signaling pathways that phosphorylates p38 MAPK and JNK in response to mitogenic and cellular stress queues. MEK4 is overexpressed and induces metastasis in advanced prostate cancer lesions. However, the value of MEK4 as an oncology target has not been pharmacologically validated because selective chemical probes targeting MEK4 have not been developed. Optimization of this series via structure–activity relationships and molecular modeling led to the identification of compound 6 ff (4-(6-fluoro-2H-indazol-3-yl)benzoic acid), a highly potent and selective MEK4 inhibitor. This series of inhibitors is the first of its kind in both activity and selectivity and will be useful in further defining the role of MEK4 in prostate and other cancers.
BICYCLIC NITROGEN-CONTAINING HETEROCYCLIC COMPOUNDS
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Page/Page column 39-40, (2010/03/02)
A nitrogen-containing bicyclic heterocyclic compound represented by the following formula (1) is provided. When the compound or a salt thereof is administered to a human being or an animal, the compound has a strong antagonistic action against EP1 recepto
